Investigating the relationship between thalamic iron concentration and disease severity in secondary progressive multiple sclerosis using quantitative susceptibility mapping: Cross-sectional analysis from the MS-STAT2 randomised controlled trial.

Background: Deep grey matter pathology is a key driver of disability worsening in people with multiple sclerosis. Quantitative susceptibility mapping (QSM) is an advanced magnetic resonance imaging (MRI) technique which quantifies local magnetic susceptibility from variations in phase produced by changes in the local magnetic field. In the deep grey matter, susceptibility has previously been validated against tissue iron concentration. However, it currently remains unknown whether susceptibility is abnormal in older progressive MS cohorts, and whether it correlates with disability. Objectives: To investigate differences in mean regional susceptibility in deep grey matter between people with secondary progressive multiple sclerosis (SPMS) and healthy controls; to examine in patients the relationships between deep grey matter susceptibility and clinical and imaging measures of disease severity. Methods: Baseline data from a subgroup of the MS-STAT2 trial (simvastatin vs. placebo in SPMS, NCT03387670) were included. The subgroup underwent clinical assessments and an advanced MRI protocol at 3T. A cohort of age-matched healthy controls underwent the same MRI protocol. Susceptibility maps were reconstructed using a robust QSM pipeline from multi-echo 3D gradient-echo sequence. Regions of interest (ROIs) in the thalamus, globus pallidus and putamen were segmented from 3D T1-weighted images, and lesions segmented from 3D fluid-attenuated inversion recovery images. Linear regression was used to compare susceptibility from ROIs between patients and controls, adjusting for age and sex. Where significant differences were found, we further examined the associations between ROI susceptibility and clinical and imaging measures of MS severity. Results: 149 SPMS (77% female; mean age: 53 yrs; median Expanded Disability Status Scale (EDSS): 6.0 [interquartile range 4.5-6.0]) and 33 controls (52% female, mean age: 57) were included.Thalamic susceptibility was significantly lower in SPMS compared to controls: mean (SD) 28.6 (12.8) parts per billion (ppb) in SPMS vs. 39.2 (12.7) ppb in controls; regression coefficient: -12.0 [95% confidence interval: -17.0 to -7.1], p < 0.001. In contrast, globus pallidus and putamen susceptibility were similar between both groups.In SPMS, a 10 ppb lower thalamic susceptibility was associated with a +0.13 [+0.01 to +0.24] point higher EDSS (p < 0.05), a -2.4 [-3.8 to -1.0] point lower symbol digit modality test (SDMT, p = 0.001), and a -2.4 [-3.7 to -1.1] point lower Sloan low contrast acuity, 2.5% (p < 0.01).Lower thalamic susceptibility was also strongly associated with a higher T2 lesion volume (T2LV, p < 0.001) and lower normalised whole brain, deep grey matter and thalamic volumes (all p < 0.001). Conclusions: The reduced thalamic susceptibility found in SPMS compared to controls suggests that thalamic iron concentrations are lower at this advanced stage of the disease. The observed relationships between lower thalamic susceptibility and more severe physical, cognitive and visual disability suggests that reductions in thalamic iron may correlate with important mechanisms of clinical disease progression. Such mechanisms appear to intimately link reductions in thalamic iron with higher T2LV and the development of thalamic atrophy, encouraging further research into QSM-derived thalamic susceptibility as a biomarker of disease severity in SPMS.

Improving criteria for dissemination in space in multiple sclerosis by including additional regions.

OBJECTIVE: We investigated the effects of adding regions to current dissemination in space (DIS) criteria for multiple sclerosis (MS). METHODS: Participants underwent brain, optic nerve, and spinal cord MRI. Baseline DIS was assessed by 2017 McDonald criteria and versions including optic nerve, temporal lobe, or corpus callosum as a fifth region (requiring 2/5), a version with all regions (requiring 3/7) and optic nerve variations requiring 3/5 and 4/5 regions. Performance was evaluated against MS diagnosis (2017 McDonald criteria) during follow-up. RESULTS: Eighty-four participants were recruited (53F, 32.8 ± 7.1 years). 2017 McDonald DIS criteria were 87% sensitive (95% CI: 76-94), 73% specific (50-89), and 83% accurate (74-91) in identifying MS. Modified criteria with optic nerve improved sensitivity to 98% (91-100), with specificity 33% (13-59) and accuracy 84% (74-91). Criteria including temporal lobe showed sensitivity 94% (84-98), specificity 50% (28-72), and accuracy 82% (72-90); criteria including corpus callosum showed sensitivity 90% (80-96), specificity 68% (45-86), and accuracy 85% (75-91). Criteria adding all three regions (3/7 required) had sensitivity 95% (87-99), specificity 55% (32-76), and accuracy 85% (75-91). When requiring 3/5 regions (optic nerve as the fifth), sensitivity was 82% (70-91), specificity 77% (55-92), and accuracy 81% (71-89); with 4/5 regions, sensitivity was 56% (43-69), specificity 95% (77-100), and accuracy 67% (56-77). INTERPRETATION: Optic nerve inclusion increased sensitivity while lowering specificity. Increasing required regions in optic nerve criteria increased specificity and decreased sensitivity. Results suggest considering the optic nerve for DIS. An option of 3/5 or 4/5 regions preserved specificity, and criteria adding all three regions had highest accuracy.

Improving explanation of motor disability with diffusion-based graph metrics at onset of the first demyelinating event.

BACKGROUND: Conventional magnetic resonance imaging (MRI) does not account for all disability in multiple sclerosis. OBJECTIVE: The objective was to assess the ability of graph metrics from diffusion-based structural connectomes to explain motor function beyond conventional MRI in early demyelinating clinically isolated syndrome (CIS). METHODS: A total of 73 people with CIS underwent conventional MRI, diffusion-weighted imaging and clinical assessment within 3 months from onset. A total of 28 healthy controls underwent MRI. Structural connectomes were produced. Differences between patients and controls were explored; clinical associations were assessed in patients. Linear regression models were compared to establish relevance of graph metrics over conventional MRI. RESULTS: Local efficiency (p = 0.045), clustering (p = 0.034) and transitivity (p = 0.036) were reduced in patients. Higher assortativity was associated with higher Expanded Disability Status Scale (EDSS) (ß = 74.9, p = 0.026) scores. Faster timed 25-foot walk (T25FW) was associated with higher assortativity (ß = 5.39, p = 0.026), local efficiency (ß = 27.1, p = 0.041) and clustering (ß = 36.1, p = 0.032) and lower small-worldness (ß = -3.27, p = 0.015). Adding graph metrics to conventional MRI improved EDSS (p = 0.045, ΔR2 = 4) and T25FW (p < 0.001, ΔR2 = 13.6) prediction. CONCLUSION: Graph metrics are relevant early in demyelination. They show differences between patients and controls and have relationships with clinical outcomes. Segregation (local efficiency, clustering, transitivity) was particularly relevant. Combining graph metrics with conventional MRI better explained disability.

Optic chiasm involvement in multiple sclerosis, aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein-associated disease.

BACKGROUND: Optic neuritis (ON) is a common feature of inflammatory demyelinating diseases (IDDs) such as multiple sclerosis (MS), aquaporin 4-antibody neuromyelitis optica spectrum disorder (AQP4 + NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). However, the involvement of the optic chiasm (OC) in IDD has not been fully investigated. AIMS: To examine OC differences in non-acute IDD patients with (ON+) and without ON (ON-) using magnetisation transfer ratio (MTR), to compare differences between MS, AQP4 + NMOSD and MOGAD and understand their associations with other neuro-ophthalmological markers. METHODS: Twenty-eight relapsing-remitting multiple sclerosis (RRMS), 24 AQP4 + NMOSD, 28 MOGAD patients and 32 healthy controls (HCs) underwent clinical evaluation, MRI and optical coherence tomography (OCT) scan. Multivariable linear regression models were applied. RESULTS: ON + IDD patients showed lower OC MTR than HCs (28.87 ± 4.58 vs 31.65 ± 4.93; p = 0.004). When compared with HCs, lower OC MTR was found in ON + AQP4 + NMOSD (28.55 ± 4.18 vs 31.65 ± 4.93; p = 0.020) and MOGAD (28.73 ± 4.99 vs 31.65 ± 4.93; p = 0.007) and in ON- AQP4 + NMOSD (28.37 ± 7.27 vs 31.65 ± 4.93; p = 0.035). ON+ RRMS had lower MTR than ON- RRMS (28.87 ± 4.58 vs 30.99 ± 4.76; p = 0.038). Lower OC MTR was associated with higher number of ON (regression coefficient (RC) = -1.15, 95% confidence interval (CI) = -1.819 to -0.490, p = 0.001), worse visual acuity (RC = -0.026, 95% CI = -0.041 to -0.011, p = 0.001) and lower peripapillary retinal nerve fibre layer (pRNFL) thickness (RC = 1.129, 95% CI = 0.199 to 2.059, p = 0.018) when considering the whole IDD group. CONCLUSION: OC microstructural damage indicates prior ON in IDD and is linked to reduced vision and thinner pRNFL.

What contributes to disability in progressive MS? A brain and cervical cord-matched quantitative MRI study.

BACKGROUND: We assessed the ability of a brain-and-cord-matched quantitative magnetic resonance imaging (qMRI) protocol to differentiate patients with progressive multiple sclerosis (PMS) from controls, in terms of normal-appearing (NA) tissue abnormalities, and explain disability. METHODS: A total of 27 patients and 16 controls were assessed on the Expanded Disability Status Scale (EDSS), 25-foot timed walk (TWT), 9-hole peg (9HPT) and symbol digit modalities (SDMT) tests. All underwent 3T brain and (C2-C3) cord structural imaging and qMRI (relaxometry, quantitative magnetisation transfer, multi-shell diffusion-weighted imaging), using a fast brain-and-cord-matched protocol with brain-and-cord-unified imaging readouts. Lesion and NA-tissue volumes and qMRI metrics reflecting demyelination and axonal loss were obtained. Random forest analyses identified the most relevant volumetric/qMRI measures to clinical outcomes. Confounder-adjusted linear regression estimated the actual MRI-clinical associations. RESULTS: Several qMRI/volumetric differences between patients and controls were observed (p < 0.01). Higher NA-deep grey matter quantitative-T1 (EDSS: beta = 7.96, p = 0.006; 9HPT: beta = -0.09, p = 0.004), higher NA-white matter orientation dispersion index (TWT: beta = -3.21, p = 0.005; SDMT: beta = -847.10, p < 0.001), lower whole-cord bound pool fraction (9HPT: beta = 0.79, p = 0.001) and higher NA-cortical grey matter quantitative-T1 (SDMT = -94.31, p < 0.001) emerged as particularly relevant predictors of greater disability. CONCLUSION: Fast brain-and-cord-matched qMRI protocols are feasible and identify demyelination - combined with other mechanisms - as key for disability accumulation in PMS.

Associations between cortical lesions, optic nerve damage, and disability at the onset of multiple sclerosis: insights into neurodegenerative processes.

BACKGROUND: Multiple sclerosis cortical lesions are areas of demyelination and neuroaxonal loss. Retinal layer thickness, measured with optical coherence tomography (OCT), is an emerging biomarker of neuroaxonal loss. Studies have reported correlations between cortical lesions and retinal layer thinning in established multiple sclerosis, suggesting a shared pathophysiological process. Here, we assessed the correlation between cortical lesions and OCT metrics at the onset of multiple sclerosis, examining, for the first time, associations with physical or cognitive disability. OBJECTIVE: To examine the relationship between cortical lesions, optic nerve and retinal layer thicknesses, and physical and cognitive disability at the first demyelinating event. METHODS: Thirty-nine patients and 22 controls underwent 3T-MRI, optical coherence tomography, and clinical tests. We identified cortical lesions on phase-sensitive inversion recovery sequences, including occipital cortex lesions. We measured the estimated total intracranial volume and the white matter lesion volume. OCT metrics included peripapillary retinal nerve fibre layer (pRNFL), ganglion cell and inner plexiform layer (GCIPL) and inner nuclear layer (INL) thicknesses. RESULTS: Higher total cortical and leukocortical lesion volumes correlated with thinner pRNFL (B = -0.0005, 95 % CI -0.0008 to -0.0001, p = 0.01; B = -0.0005, 95 % CI -0.0008 to -0.0001, p = 0.01, respectively). Leukocortical lesion number correlated with colour vision deficits (B = 0.58, 95 %CI 0.039 to 1,11, p = 0.036). Thinner GCIPL correlated with a higher Expanded Disability Status Scale (B = -0.06, 95 % CI -1.1 to -0.008, p = 0.026). MS diagnosis (n = 18) correlated with higher cortical and leukocortical lesion numbers (p = 0.004 and p = 0.003), thinner GCIPL (p = 0.029) and INL (p = 0.041). CONCLUSION: The association between cortical lesions and axonal damage in the optic nerve reinforces the role of neurodegenerative processes in MS pathogenesis at onset.

Cardiovascular risk factors in secondary progressive multiple sclerosis: A cross-sectional analysis from the MS-STAT2 randomized controlled trial.

BACKGROUND AND PURPOSE: There is increasing evidence that cardiovascular risk (CVR) contributes to disability progression in multiple sclerosis (MS). CVR is particularly prevalent in secondary progressive MS (SPMS) and can be quantified through validated composite CVR scores. The aim was to examine the cross-sectional relationships between excess modifiable CVR, whole and regional brain atrophy on magnetic resonance imaging, and disability in patients with SPMS. METHODS: Participants had SPMS, and data were collected at enrolment into the MS-STAT2 trial. Composite CVR scores were calculated using the QRISK3 software. Prematurely achieved CVR due to modifiable risk factors was expressed as QRISK3 premature CVR, derived through reference to the normative QRISK3 dataset and expressed in years. Associations were determined with multiple linear regressions. RESULTS: For the 218 participants, mean age was 54 years and median Expanded Disability Status Scale was 6.0. Each additional year of prematurely achieved CVR was associated with a 2.7 mL (beta coefficient; 95% confidence interval 0.8-4.7; p = 0.006) smaller normalized whole brain volume. The strongest relationship was seen for the cortical grey matter (beta coefficient 1.6 mL per year; 95% confidence interval 0.5-2.7; p = 0.003), and associations were also found with poorer verbal working memory performance. Body mass index demonstrated the strongest relationships with normalized brain volumes, whilst serum lipid ratios demonstrated strong relationships with verbal and visuospatial working memory performance. CONCLUSIONS: Prematurely achieved CVR is associated with lower normalized brain volumes in SPMS. Future longitudinal analyses of this clinical trial dataset will be important to determine whether CVR predicts future disease worsening.

Feasibility of in vivo multi-parametric quantitative magnetic resonance imaging of the healthy sciatic nerve with a unified signal readout protocol.

Magnetic resonance neurography (MRN) has been used successfully over the years to investigate the peripheral nervous system (PNS) because it allows early detection and precise localisation of neural tissue damage. However, studies demonstrating the feasibility of combining MRN with multi-parametric quantitative magnetic resonance imaging (qMRI) methods, which provide more specific information related to nerve tissue composition and microstructural organisation, can be invaluable. The translation of emerging qMRI methods previously validated in the central nervous system to the PNS offers real potential to characterise in patients in vivo the underlying pathophysiological mechanisms involved in a plethora of conditions of the PNS. The aim of this study was to assess the feasibility of combining MRN with qMRI to measure diffusion, magnetisation transfer and relaxation properties of the healthy sciatic nerve in vivo using a unified signal readout protocol. The reproducibility of the multi-parametric qMRI protocol as well as normative qMRI measures in the healthy sciatic nerve are reported. The findings presented herein pave the way to the practical implementation of joint MRN-qMRI in future studies of pathological conditions affecting the PNS.

Patterns of inflammation, microstructural alterations, and sodium accumulation define multiple sclerosis subtypes after 15 years from onset.

Introduction: Conventional MRI is routinely used for the characterization of pathological changes in multiple sclerosis (MS), but due to its lack of specificity is unable to provide accurate prognoses, explain disease heterogeneity and reconcile the gap between observed clinical symptoms and radiological evidence. Quantitative MRI provides measures of physiological abnormalities, otherwise invisible to conventional MRI, that correlate with MS severity. Analyzing quantitative MRI measures through machine learning techniques has been shown to improve the understanding of the underlying disease by better delineating its alteration patterns. Methods: In this retrospective study, a cohort of healthy controls (HC) and MS patients with different subtypes, followed up 15 years from clinically isolated syndrome (CIS), was analyzed to produce a multi-modal set of quantitative MRI features encompassing relaxometry, microstructure, sodium ion concentration, and tissue volumetry. Random forest classifiers were used to train a model able to discriminate between HC, CIS, relapsing remitting (RR) and secondary progressive (SP) MS patients based on these features and, for each classification task, to identify the relative contribution of each MRI-derived tissue property to the classification task itself. Results and discussion: Average classification accuracy scores of 99 and 95% were obtained when discriminating HC and CIS vs. SP, respectively; 82 and 83% for HC and CIS vs. RR; 76% for RR vs. SP, and 79% for HC vs. CIS. Different patterns of alterations were observed for each classification task, offering key insights in the understanding of MS phenotypes pathophysiology: atrophy and relaxometry emerged particularly in the classification of HC and CIS vs. MS, relaxometry within lesions in RR vs. SP, sodium ion concentration in HC vs. CIS, and microstructural alterations were involved across all tasks.

Aberrant olfactory network functional connectivity in people with olfactory dysfunction following COVID-19 infection: an exploratory, observational study.

Background: Olfactory impairments and anosmia from COVID-19 infection typically resolve within 2-4 weeks, although in some cases, symptoms persist longer. COVID-19-related anosmia is associated with olfactory bulb atrophy, however, the impact on cortical structures is relatively unknown, particularly in those with long-term symptoms. Methods: In this exploratory, observational study, we studied individuals who experienced COVID-19-related anosmia, with or without recovered sense of smell, and compared against individuals with no prior COVID-19 infection (confirmed by antibody testing, all vaccine naïve). MRI Imaging was carried out between the 15th July and 17th November 2020 at the Queen Square House Clinical Scanning Facility, UCL, United Kingdom. Using functional magnetic resonance imaging (fMRI) and structural imaging, we assessed differences in functional connectivity (FC) between olfactory regions, whole brain grey matter (GM) cerebral blood flow (CBF) and GM density. Findings: Individuals with anosmia showed increased FC between the left orbitofrontal cortex (OFC), visual association cortex and cerebellum and FC reductions between the right OFC and dorsal anterior cingulate cortex compared to those with no prior COVID-19 infection (p < 0.05, from whole brain statistical parametric map analysis). Individuals with anosmia also showed greater CBF in the left insula, hippocampus and ventral posterior cingulate when compared to those with resolved anosmia (p < 0.05, from whole brain statistical parametric map analysis). Interpretation: This work describes, for the first time to our knowledge, functional differences within olfactory areas and regions involved in sensory processing and cognitive functioning. This work identifies key areas for further research and potential target sites for therapeutic strategies. Funding: This study was funded by the National Institute for Health and Care Research and supported by the Queen Square Scanner business case.

Multimodal Analysis of the Visual Pathways in Friedreich's Ataxia Reveals Novel Biomarkers.

BACKGROUND: Optic neuropathy is a near ubiquitous feature of Friedreich's ataxia (FRDA). Previous studies have examined varying aspects of the anterior and posterior visual pathways but none so far have comprehensively evaluated the heterogeneity of degeneration across different areas of the retina, changes to the macula layers and combined these with volumetric MRI studies of the visual cortex and frataxin level. METHODS: We investigated 62 genetically confirmed FRDA patients using an integrated approach as part of an observational cohort study. We included measurement of frataxin protein levels, clinical evaluation of visual and neurological function, optical coherence tomography to determine retinal nerve fibre layer thickness and macular layer volume and volumetric brain MRI. RESULTS: We demonstrate that frataxin level correlates with peripapillary retinal nerve fibre layer thickness and that retinal sectors differ in their degree of degeneration. We also shown that retinal nerve fibre layer is thinner in FRDA patients than controls and that this thinning is influenced by the AAO and GAA1. Furthermore we show that the ganglion cell and inner plexiform layers are affected in FRDA. Our MRI data indicate that there are borderline correlations between retinal layers and areas of the cortex involved in visual processing. CONCLUSION: Our study demonstrates the uneven distribution of the axonopathy in the retinal nerve fibre layer and highlight the relative sparing of the papillomacular bundle and temporal sectors. We show that thinning of the retinal nerve fibre layer is associated with frataxin levels, supporting the use the two biomarkers in future clinical trials design. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Optimized multi-echo gradient-echo magnetic resonance imaging for gray and white matter segmentation in the lumbosacral cord at 3 T.

Atrophy in the spinal cord (SC), gray (GM) and white matter (WM) is typically measured in-vivo by image segmentation on multi-echo gradient-echo magnetic resonance images. The aim of this study was to establish an acquisition and analysis protocol for optimal SC and GM segmentation in the lumbosacral cord at 3 T. Ten healthy volunteers underwent imaging of the lumbosacral cord using a 3D spoiled multi-echo gradient-echo sequence (Siemens FLASH, with 5 echoes and 8 repetitions) on a Siemens Prisma 3 T scanner. Optimal numbers of successive echoes and signal averages were investigated comparing signal-to-noise (SNR) and contrast-to-noise ratio (CNR) values as well as qualitative ratings for segmentability by experts. The combination of 5 successive echoes yielded the highest CNR between WM and cerebrospinal fluid and the highest rating for SC segmentability. The combination of 3 and 4 successive echoes yielded the highest CNR between GM and WM and the highest rating for GM segmentability in the lumbosacral enlargement and conus medullaris, respectively. For segmenting the SC and GM in the same image, we suggest combining 3 successive echoes. For SC or GM segmentation only, we recommend combining 5 or 3 successive echoes, respectively. Six signal averages yielded good contrast for reliable SC and GM segmentation in all subjects. Clinical applications could benefit from these recommendations as they allow for accurate SC and GM segmentation in the lumbosacral cord.

Multi-echo quantitative susceptibility mapping: how to combine echoes for accuracy and precision at 3 Tesla.

PURPOSE: To compare different multi-echo combination methods for MRI QSM. Given the current lack of consensus, we aimed to elucidate how to optimally combine multi-echo gradient-recalled echo signal phase information, either before or after applying Laplacian-base methods (LBMs) for phase unwrapping or background field removal. METHODS: Multi-echo gradient-recalled echo data were simulated in a numerical head phantom, and multi-echo gradient-recalled echo images were acquired at 3 Tesla in 10 healthy volunteers. To enable image-based estimation of gradient-recalled echo signal noise, 5 volunteers were scanned twice in the same session without repositioning. Five QSM processing pipelines were designed: 1 applied nonlinear phase fitting over TEs before LBMs; 2 applied LBMs to the TE-dependent phase and then combined multiple TEs via either TE-weighted or SNR-weighted averaging; and 2 calculated TE-dependent susceptibility maps via either multi-step or single-step QSM and then combined multiple TEs via magnitude-weighted averaging. Results from different pipelines were compared using visual inspection; summary statistics of susceptibility in deep gray matter, white matter, and venous regions; phase noise maps (error propagation theory); and, in the healthy volunteers, regional fixed bias analysis (Bland-Altman) and regional differences between the means (nonparametric tests). RESULTS: Nonlinearly fitting the multi-echo phase over TEs before applying LBMs provided the highest regional accuracy of χ $$ \chi $$ and the lowest phase noise propagation compared to averaging the LBM-processed TE-dependent phase. This result was especially pertinent in high-susceptibility venous regions. CONCLUSION: For multi-echo QSM, we recommend combining the signal phase by nonlinear fitting before applying LBMs.

Comparison of multicenter MRI protocols for visualizing the spinal cord gray matter.

PURPOSE: Spinal cord gray-matter imaging is valuable for a number of applications, but remains challenging. The purpose of this work was to compare various MRI protocols at 1.5 T, 3 T, and 7 T for visualizing the gray matter. METHODS: In vivo data of the cervical spinal cord were collected from nine different imaging centers. Data processing consisted of automatically segmenting the spinal cord and its gray matter and co-registering back-to-back scans. We computed the SNR using two methods (SNR_single using a single scan and SNR_diff using the difference between back-to-back scans) and the white/gray matter contrast-to-noise ratio per unit time. Synthetic phantom data were generated to evaluate the metrics performance. Experienced radiologists qualitatively scored the images. We ran the same processing on an open-access multicenter data set of the spinal cord MRI (N = 267 participants). RESULTS: Qualitative assessments indicated comparable image quality for 3T and 7T scans. Spatial resolution was higher at higher field strength, and image quality at 1.5 T was found to be moderate to low. The proposed quantitative metrics were found to be robust to underlying changes to the SNR and contrast; however, the SNR_single method lacked accuracy when there were excessive partial-volume effects. CONCLUSION: We propose quality assessment criteria and metrics for gray-matter visualization and apply them to different protocols. The proposed criteria and metrics, the analyzed protocols, and our open-source code can serve as a benchmark for future optimization of spinal cord gray-matter imaging protocols.

Assessing Lumbar Plexus and Sciatic Nerve Damage in Relapsing-Remitting Multiple Sclerosis Using Magnetisation Transfer Ratio.

Background: Multiple sclerosis (MS) has traditionally been regarded as a disease confined to the central nervous system (CNS). However, neuropathological, electrophysiological, and imaging studies have demonstrated that the peripheral nervous system (PNS) is also involved, with demyelination and, to a lesser extent, axonal degeneration representing the main pathophysiological mechanisms. Aim: The purpose of this study was to assess PNS damage at the lumbar plexus and sciatic nerve anatomical locations in people with relapsing-remitting MS (RRMS) and healthy controls (HCs) in vivo using magnetisation transfer ratio (MTR), which is a known imaging biomarker sensitive to alterations in myelin content in neural tissue, and not previously explored in the context of PNS damage in MS. Method: Eleven HCs (7 female, mean age 33.6 years, range 24-50) and 15 people with RRMS (12 female, mean age 38.5 years, range 30-56) were recruited for this study and underwent magnetic resonance imaging (MRI) investigations together with clinical assessments using the expanded disability status scale (EDSS). Magnetic resonance neurography (MRN) was first used for visualisation and identification of the lumbar plexus and the sciatic nerve and MTR imaging was subsequently performed using identical scan geometry to MRN, enabling straightforward co-registration of all data to obtain global and regional mean MTR measurements. Linear regression models were used to identify differences in MTR values between HCs and people with RRMS and to identify an association between MTR measures and EDSS. Results: MTR values in the sciatic nerve of people with RRMS were found to be significantly lower compared to HCs, but no significant MTR changes were identified in the lumbar plexus of people with RRMS. The median EDSS in people with RRMS was 2.0 (range, 0-3). No relationship between the MTR measures in the PNS and EDSS were identified at any of the anatomical locations studied in this cohort of people with RRMS. Conclusion: The results from this study demonstrate the presence of PNS damage in people with RRMS and support the notion that these changes, suggestive of demyelination, maybe occurring independently at different anatomical locations within the PNS. Further investigations to confirm these findings and to clarify the pathophysiological basis of these alterations are warranted.

Magnetisation transfer ratio combined with magnetic resonance neurography is feasible in the proximal lumbar plexus using healthy volunteers at 3T.

Magnetic resonance neurography (MRN) has been used extensively to study pathological conditions affecting the peripheral nervous system (PNS). However, tissue damage is assessed qualitatively with little information regarding the underlying pathophysiological processes involved. Magnetisation transfer ratio (MTR) is a quantitative magnetic resonance imaging method which is sensitive to tissue macromolecular content and may therefore have an important role in the study of pathologies affecting the PNS. This study explored the feasibility of obtaining reliable MTR measurements in the proximal lumbar plexus of healthy volunteers using MRN to identify and segment each lumbar segment (L2-L5) and regions (preganglionic, ganglionic and postganglionic). Reproducibility of the MTR measurements and of the segmentation method were assessed from repeated measurements (scan-rescan), and from the reanalysis of images (intra- and inter-rater assessment), by calculating the coefficient of variation (COV). In all segments combined (L2-L5), mean (± SD) MTR was 30.5 (± 2.4). Scan-rescan, intra- and inter-rater COV values were 3.2%, 4.4% and 5.3%, respectively. One-way analysis of variance revealed a statistically significant difference in MTR between the preganglionic and postganglionic regions in all lumbar segments. This pilot study in healthy volunteers demonstrates the feasibility of obtaining reliable MTR measurements in the proximal lumbar plexus, opening up the possibility of studying a broad spectrum of neurological conditions in vivo.

Reduced accuracy of MRI deep grey matter segmentation in multiple sclerosis: an evaluation of four automated methods against manual reference segmentations in a multi-center cohort.

BACKGROUND: Deep grey matter (DGM) atrophy in multiple sclerosis (MS) and its relation to cognitive and clinical decline requires accurate measurements. MS pathology may deteriorate the performance of automated segmentation methods. Accuracy of DGM segmentation methods is compared between MS and controls, and the relation of performance with lesions and atrophy is studied. METHODS: On images of 21 MS subjects and 11 controls, three raters manually outlined caudate nucleus, putamen and thalamus; outlines were combined by majority voting. FSL-FIRST, FreeSurfer, Geodesic Information Flow and volBrain were evaluated. Performance was evaluated volumetrically (intra-class correlation coefficient (ICC)) and spatially (Dice similarity coefficient (DSC)). Spearman's correlations of DSC with global and local lesion volume, structure of interest volume (ROIV), and normalized brain volume (NBV) were assessed. RESULTS: ICC with manual volumes was mostly good and spatial agreement was high. MS exhibited significantly lower DSC than controls for thalamus and putamen. For some combinations of structure and method, DSC correlated negatively with lesion volume or positively with NBV or ROIV. Lesion-filling did not substantially change segmentations. CONCLUSIONS: Automated methods have impaired performance in patients. Performance generally deteriorated with higher lesion volume and lower NBV and ROIV, suggesting that these may contribute to the impaired performance.

Sodium in the Relapsing-Remitting Multiple Sclerosis Spinal Cord: Increased Concentrations and Associations With Microstructural Tissue Anisotropy.

BACKGROUND: Associations between brain total sodium concentration, disability, and disease progression have recently been reported in multiple sclerosis. However, such measures in spinal cord have not been reported. PURPOSE: To measure total sodium concentration (TSC) alterations in the cervical spinal cord of people with relapsing-remitting multiple sclerosis (RRMS) and a control cohort using sodium MR spectroscopy (MRS). STUDY TYPE: Retrospective cohort. SUBJECTS: Nineteen people with RRMS and 21 healthy controls. FIELD STRENGTH/SEQUENCE: 3 T sodium MRS, diffusion tensor imaging, and 3D gradient echo. ASSESSMENT: Quantification of total sodium concentration in the cervical cord using a reference phantom. Measures of spinal cord cross-sectional area, fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity from 1 H MRI. Clinical assessments of 9-Hole Peg Test, 25-Foot Timed walk test, Paced Auditory Serial Addition Test with 3-second intervals, grip strength, vibration sensitivity, and posturography were performed on the RRMS cohort as well as reporting lesions in the C2/3 area. STATISTICAL TESTS: Multiple linear regression models were run between sodium and clinical scores, cross-sectional area, and diffusion metrics to establish any correlations. RESULTS: A significant increase in spinal cord total sodium concentration was found in people with RRMS relative to healthy controls (57.6 ± 18 mmol and 38.0 ± 8.6 mmol, respectively, P < 0.001). Increased TSC correlated with reduced fractional anisotropy (P = 0.034) and clinically with decreased mediolateral stability assessed with posturography (P = 0.045). DATA CONCLUSION: Total sodium concentration in the cervical spinal cord is elevated in RRMS. This alteration is associated with reduced fractional anisotropy, which may be due to changes in tissue microstructure and, hence, in the integrity of spinal cord tissue. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Fast bound pool fraction mapping via steady-state magnetization transfer saturation using single-shot EPI.

PURPOSE: To enable clinical applications of quantitative magnetization transfer (qMT) imaging by developing a fast method to map one of its fundamental model parameters, the bound pool fraction (BPF), in the human brain. THEORY AND METHODS: The theory of steady-state MT in the fast-exchange approximation is used to provide measurements of BPF, and bound pool transverse relaxation time ( T2B ). A sequence that allows sampling of the signal during steady-state MT saturation is used to perform BPF mapping with a 10-min-long fully echo planar imaging-based MRI protocol, including inversion recovery T1 mapping and B1 error mapping. The approach is applied in 6 healthy subjects and 1 multiple sclerosis patient, and validated against a single-slice full qMT reference acquisition. RESULTS: BPF measurements are in agreement with literature values using off-resonance MT, with average BPF of 0.114(0.100-0.128) in white matter and 0.068(0.054-0.085) in gray matter. Median voxel-wise percentage error compared with standard single slice qMT is 4.6%. Slope and intercept of linear regression between new and reference BPF are 0.83(0.81-0.85) and 0.013(0.11-0.16). Bland-Altman plot mean bias is 0.005. In the multiple sclerosis case, the BPF is sensitive to pathological changes in lesions. CONCLUSION: The method developed provides accurate BPF estimates and enables shorter scan time compared with currently available approaches, demonstrating the potential of bringing myelin sensitive measurement closer to the clinic.

Gray vs. White Matter Segmentation of the Conus Medullaris: Reliability and Variability in Healthy Volunteers.

BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI)-derived spinal cord (SC) gray and white matter (GM/WM) volume are useful indirect measures of atrophy and neurodegeneration over time, typically obtained in the upper SC. Neuropathological evidence suggests that in certain neurological conditions, early degeneration may occur as low as the sacral SC. In this study, the feasibility of GM/WM segmentation of the conus medullaris (CM) was assessed in vivo. METHODS: Twenty-three healthy volunteers (11 female, mean age 47 years) underwent high-resolution 3T MRI of the CM using a 3-dimensional fast field echo sequence. Reproducibility of the volume measurements was assessed in 5 subjects (2 female, 25-37 years) by one rater who repeated the analysis 3 times and also with 2 additional raters working independently in order to calculate the intra- and interrater coefficient of variation (COV), respectively. Furthermore, the influence of age, gender, spine and SC metrics on tissue-specific measures of the CM was investigated. RESULTS: Volumetric CM analyses (N = 23) for the SC, GM, and WM revealed a mean (SD) total volume of CM-TV = 1746.9 (296.7) mm3 , CM-GM-TV = 731.2 (106.0) mm3 , and CM-WM-TV = 1014.6 (211.3) mm3 , respectively. The intra-rater COV for measuring the CM-TV and CM-GM-TV was 3.38% and 7.42%, respectively; the interrater COV was 3.43% and 10.80%, respectively. Using age, gender, spine and SC metrics in regression models substantially reduced group variability for CM-TV, CM-WM-TV, and CM-GM-TV by up to 39.2%, 42.7%, and 21.2%, respectively. CONCLUSIONS: The results from this study demonstrate the feasibility of obtaining tissue-specific volume measurements in the CM by means of MRI with good reproducibility and provide normative data for future applications in neurological diseases affecting the lower SC.